A multilayer depth-of-interaction positron emission tomography (DOI-PET) detector with an independent readout structure has a potential advantage as a time-of-flight (TOF)-PET detector. The thin scintillator block of each detector layer can afford an improved coincidence time resolution (CTR) of ∼100 ps because the photon transfer time spread within the scintillator inherently decreases. To evaluate the potential TOF capabilities of a multilayer DOI-PET detector, which consists of thin layers of a cerium-doped lutetium–yttrium oxyorthosilicate (LYSO:Ce) scintillator coupled to a multi-pixel photon counter (MPPC) array, we examined the detector’s CTR performance via Monte Carlo simulations. We used several types of scintillator structures: a monolithic plate, laser-processing array with 3.2 mm pitch, fine laser-processing array with 1.6 mm pitch, and pixelated array with 3.2 mm pitch, with 2, 4, 6, and 8 mm thickness values of a 25.6 mm × 25.6 mm scintillator cross-section. The MPPC array was composed of 3.0 mm × 3.0 mm photosensitive segments arranged in an 8 × 8 array. Here, we note that the CTR performance also significantly depends on the timing detection method, which generates a timing trigger signal for coincidence detection. Thus, we evaluated the CTRs for each scintillator structure by adopting four timing detection methods: using the total sum signal of 64 MPPC chips (T_sum), the maximum signal in the 64 MPPC chips (Max), the sum signal of a partial number of MPPC chips located at and in the vicinity of the γ-ray interaction position (P_sum), and the average of the timestamps generated at several MPPC chips (Ave). When using the T_sum for timing detection, the CTR full width at half-maximum values were ∼100 ps regardless of the scintillator structure. However, when using the Max signal approach, the CTRs of the monolithic plates, laser-processing arrays, and fine-pitch laser-processing arrays were drastically degraded with increasing thickness. On the other hand, the CTRs of the pixelated arrays exhibited almost no degradation. To improve the CTRs of the monolithic plate and the (fine-pitch) laser-processing array that exhibit a large light spread in the scintillator block, we applied the P_sum and Ave methods. The resulting CTRs significantly improved upon using P_sum; however, in the Ave approach the improvement effect disappeared when the thickness was <6 mm in case of our simulation.